3beta-substituted-4-pregnenes



United States Patent 3,398,142 3fl-SUBSTlTUTED-4-PREGNENES David J.Marshall, Cote St. Luc, Quebec, Canada, assignor to American HomeProducts Corporation, New York, N.Y., a corporation of Delaware NoDrawing. Filed June 10, 1963, Ser. No. 286,475 Claims priority,applicatiozngfauada, June 23, 1962,

3 Claims. 61. 260-23955) The present invention relates to3/8-su'bstituted-4-pregnenes of the following general structuralformula:

in which R is selected from the group consisting of hydrogen and loweracyl and X, Y, and Z are defined as follows:

These compounds are useful progestational compounds possessing a highdegree of activity when administered orally or by subcutaneous injectionand are also of long duration of action. Furthermore, the compounds ofthe present invention are distinguished by being substantially free fromundesirable side-effects such as, e.g., masculinizing properties. Someof these compounds possess the singular property of suppressing theaction of pituary gonadotrophin. Surprisingly, some of the3fl-hydroxy-4- pregnenes of the present invention are more active asprogestational agents than the corresponding A -3-ket0nes.

As hereinbefore mentioned, the compounds of the present invention may beadministered orally or by intramuscular injection. For administration byintramuscular injection, the compounds of the present invention aredissolved in a pharmaceutically acceptable solvent, for example, in avegetable oil, preferably in dosages of from 1 to 50 mg. per dosageform. For oral administration, the compounds of the present inventionmay be formulated with pharmaceutically acceptable carriers, forexample, lactose, starch, magnesium stearate, or the like, for instance,in the form of tablets or capsules, preferably in dosages containingfrom 5 to 50 mg. of the active ingredient per dosage form.

This invention also relates to a method for producing the hereinbeforereferred to 3 p-hydroxy-4-pregnenes which are produced by treating acorrespondingly substituted progesterone with lithium aluminumtri-t-butoxyhydride or with sodium borohydride, with the new andunexpected result that the 3-keto group is smoothly reduced to a 38-hydroxy group without concomitant reduction of the ZO-keto group. Thisresult is all the more surprising because it is well known that -ketogroups are usually more readily reduced by hydrides than A -3-ketogroups 3,398,142 Patented Aug. 20, 1968 The 3p-hydroxy group of these4-pregnenes may be acylated in conventional manner to obtain thecorresponding 3fl-lower acyloxy-4-pregnenes.

The unusual and surprising course of this reaction depends upon thepresence of a suitable substituent in position 17, or in both positions16 and 17, which inhibits the reactivity of the 20l eto group towardsthe specific reducing agent, lithium aluminum tri-t-butoxyhydride orsodium borohydride. Preferred substituents are those selected from thegroup consisting of 17a-lower acyloxy, 17a-lower alkyl, :,l7ot-IOWB1alkylidenedioxy, and 16a, 17a-lower aralkylidenedioxy.

The reduction of the suitably substituted progesterone is preferablycarried out in solution in a solvent in which both the progesterone andthe reducing agent are soluble. Such a solvent can be of the ether type.A preferred solvent for the reaction is tetrahydrofuran.

Other conditions of reaction will, of course, have an effect on theyield obtained and onthe possible formation of undesirable by-products.The preferred conditions of reaction include the use of a molar excessof lithium aluminum tri-t-butoxyhydride or sodium borohydride, whilestirring, at temperatures between 0 C. and 65 C. for several hours.Larger amounts of the hydride, or longer reaction times are required atlower temperatures. After completion of the reaction, the desired 38-hydroxy- 4-pregnene may be recovered in a conventional manner from thereaction mixture. When an excess of hydride has been used, this excessmay be decomposed before recovcry of the product.

The preferred 3 9-hydroxy-4-pregnenes of the invention include:

3fi-hydroxy-17u-acetoxy-4-pregnen-20-one3/3-hydroxy-6a-methyl-17u-acetoxy-4-pregnen-20-one3fl-hydroxy-oot-fluoro-17a-acetoxy-4-pregnen-20-one 3 8-hydroxy16a,17a-isopropylidenedioxy-4-pregnen-20- one 3 ,8, 1600, 17a-trihydrOxy-4-pr6gnen-20-one acetophenonide,

and

SB-hydroxy-17a-methyl-4-pregnen-20-one.

The following formulae and examples will illustrate this invention inpreferred aspects.

in which X, Y and Z are as defined hereinbefore.

EXAMPLE 1 3,6-hydroxy-17a-acetoxy-4-pregnen-20-one A solution of 0.30 g.of 17a-acetoxyprogesterone [Turner, I. Am. Chem. Soc., 75, 3489 (1953)]in 7 ml. of tetrahy-drofuran was added dropwise with stirring to anice-cooled solution of 0.82 g. of lithium aluminum trit-butoxyhydride in3 ml. of tetrahydrofuran. After stirring for three hours in an ice bath,the mixture was hydrolysed with saturated Rochelle salt solution andfiltered, and the filtrate was evaporated in vacuo. Crystallization ofthe residue from methanol-water gave 3/3 hydroxy-17a-acetoxy-4-pregnen-20-one, M.P. 199-2015" C.,

[a] +24.5 (in chloroform). The infrared spectrum ,showed the presence ofhydroxyl and the 17u-acetoxy- 20-ketone grouping, and the absence of A-3-ketone.

Analysis.Calcd. for C H O C, 73.75; H, 9.15. Found: C, 73.98; H, 9.39.

The corresponding 3,17-diacetate, obtained by acetylation with aceticanhydride in pyridine, was crystallized from aqueous methanol, M.P.166168.5 C., [a] ]-1.1 (in chloroform).

Analysis.Calcd. for C H O C, 72.09; H, 8.71. Found: C, 72.36; H, 8.74.

A sample of l7a-acetoxyprogesterone was added to an ice-cooled solutionof sodium borohydride in dry methanol, and stirred for 1.5 hours. Twodrops of acetic acid were added, and the mixture was evaporated todryness. Extraction with chloroform, followed by evaporation of thesolvent, yielded 3B-hydroxy-17a-acetoxy-4-pregnen- 20-one.

EXAMPLE 2 3 fl-hydroxy-6u-methyll7a-acetoxy-4-pregnen-20-one A solutionof 1.50 g. of 6a-methyl-17a-acetoxy-progesferone [Babcock et al., J. Am.Chem. Soc., 80, 2904 (1958)] in 39 ml. of tetrahydrofuran was addeddropwise to 2.97 g. of lithium aluminum tri-t-butoxyhydride in 12 ml. oftetrahydrofuran. After stirring for three hours at room temperature, 12ml. of acetone was added to decompose excess hydride and stirring wascontinued for an additional thirty minutes. Sufiicient saturated sodiumsulfate solution was then added to precipitate the inorganic salts, themixture was filtered, and the filtrate was concentrated in vacuo. Etherextraction gave a crude product which was chromatographed in benzene onFlorisil (a synthetic magnesium silicate). The material eluted withbenzene containing 5% ether was crystallized from ether-hexane, yieldingthe Se -hydroxy compound, M.P.

183-186 C., [a] +21 (in chloroform).

Analysis.-Calcd. for C H O C, 74.57; H, 8.87. Found: C, 74.25; H, 9.22.

The diacetate, formed in the usual way, was crystallized from methanol,M.P. 165167 C., [u] 13 (in chloroform).

Analysis.Calcd. for C H O C, 72.52; H, 8.90. Found: C, 72.26; H, 8.60.

EXAMPLE 3 3 B-hydroxy-6a-fiuoro- 17 a-acetoxy-4-pregnen-20-one6a-fluoro-17a-acetoxyprogesterone [Bowers et al., J. Am. Chem. Soc., 81,5991 (1959)] was reduced with lithium aluminum tri-t-butoxyhyd'ride asdescribed above for the corresponding 6-methyl compound. The crudeproduct was crystallized from aqueous ethanol and then fromacetone-hexane, M.P. 148148.5 C. (dec.), [a] +27 (in chloroform).

Analysis.Calcd. for C H FO C, 70.39; H, 8.47. Found: C, 70.04; H, 8.24.

The diacetate melted at 207 C. (dec.), [a] 8.1.

Analysis.Calc-d. for C H FO C, 69.10; H, 8.12. Found: C, 69.01; H, 8.10.

EXAMPLE 4 3 fl-hydroxy- 1 6oz, 17a-isopropylidenedioxy-4- pregnen-20-one16e,17a-isopropylidenedioxyprogesterone [Cooley et al., J. Chem. Soc.,4373 (1955)] was reduced with lithium aluminum tri-t-butoxyhydride at asdescribed above for l7a-a-cetoxy-progesterone. The crude product wasacetylated and the acetate was crystallized from methylenechloride-methanol, M.P. 196197.5 C. [(1]D24+43 (in chloroform).

Analysis.Calcd. for C H O C, 72.51; H, 8.89. Found: C, 72.81; H, 9.03.

A mixture of 0.42 g. of the acetate and 0.08 g. of potassium carbonatein 6 ml. of methanol and 0.6 ml.

of water was heated for one hour under reflux; water was added, and theresulting solid was recrystallized from aqueous methanol. The3fl-hydroxy compound melted at 168170 C. (sometimes resolidifying andremelting at 184185 C.), [a] (in chloroform).

Analysis.Calcd. for C24H36O4; C, H, 9.34- Found: C, 73.94; H, 9.15.

16,17-isopropylidenedioxyprogesterone (200 mg, 0.52 millimole) was addedto an ice-cooled solution of 39 mg. (1.04 millimoles) of sodiumborohydride in 5 ml. of dry methanol. After stirring for 1.5 hours, 0.1ml. of acetic acid was added, and the solution was taken to dryness.Extraction with cholorform gave a solid product which was identified asalmost pure 3fi-hydroxy-16a,17 xisopropylidenedioxy-4-pregnen-20-one byinfrared spectrography and thin-layer chromatography.

EXAMPLE 5 3,8,16a,17a-trihydroxy-4-pregnen-20-one acetophenonide Asolution of 1.00 'g. of 16oz,17a-dihydroxy-progesterone acetophenonide[Fried et al., Chem. and Ind., 465 (1961)] in 20 ml. of tetrahydrofuranwas added to 1.70 g. of lithium aluminum tri-t-butoxyhydride in 8 ml. oftetrahydrofuran. After stirring for three hours at room temperature,sufficient saturated ammonium chloride was added to precipitate theinorganic salts, the mixture was filtered, and the filtrate wasconcentrated in vacuo. Ether extraction gave a gummy product which didnot crystallize well. It was acetylated with acetic anhydride andpyridine, and the acetate was crystallized from methylenechloride-methanol, M.P. 166168 C., [a] 12 (in ch-lo roform)Analysis.Calcd. for C H O C, 75.58; H, 8.19. Found: C, 75.50; H, 7.95.

A mixture of 0.48 g. of the acetate and 0.14 g. of potassium carbonatein 6.5 ml. of methanol and 0.6 ml. of water was heated for one hourunder reflux, and the solution was diluted with water and extracted withether. Crystallization from ether-hexane yielded3B,16u,170ttrihydroxy-4-pregnen-20-one acetophenonide, M.P. 133- 141 C.,[a] +25 (in chloroform).

Analysis.Calcd. for 0 11 0,: C, 77.29; H, 8.50. Found: C, 77.21; H,8.41.

EXAMPLE 6 3 B-hydroxy- 17a-methyl-4-pregnen-20-one Reduction of17a-methylprogesterone [Heusser et al., Helv. Chem. Acta., 33, 2229(1950)] with lithium aluminum tri-t-butoxyhydride at 0 C. as describedabove gave the corresponding 3,8-hydroxy compound, characterized by itsinfrared spectrum, which showed the presence of hydroxyl and ZO-ketoneand the absence of A -3-ketone.

I claim:

1. A compound of the formula wherein R is selected from the groupconsisting of hydrogen and lower alkanoyl, P represents lower alkyl, andQ is selected from the group consisting of lower alkyl and phenyl.

2. 3B hydroxy 16,17a isopropylidenedioxy 4 pregnen-20-one.

3. 35,1604,17m-trihydroxy-4-pre-gnen-20-one acetophenonide.

(References on following page) References Cited UNITED OTHER REFERENCESSTATES PATENTS Fieser and F ieser, Steroids, New York, Reinhold, 1959,

. page 561.

g Fried 6131., Chem. and Ind., pp. 465 and 466 (1961). at a 6 Fried 6181., Chem. and Ind., pp. 466-468 (1961).

S011man 260397.4

Babcock et a1 260-3975 H. A. FRENCH, Primary Examiner.

1. A COMPOUND OF THE FORMULA